The goal of this project is to conduct translational research aimed at developing improved and novel therapies for children with HIV infection and HIV-associated malignancies. In terms of HIV infection, both antiretroviral and immunologic approaches are currently being investigated. One focus during the past year has been to continue to evaluate in Phase I/II trials the highly active protease inhibitors indinavir and ritonavir. These drugs have been found to make a major impact on the care of adults with HIV infection, but until very recently have not been studied or available for children with HIV infection. These studies helped define the pharmacokinetics, toxicity, and activity of ritonavir and indinavir in children. Based in part on short term data from one of these trials, ritonavir was approved by the FDA for pediatric use in March 1997, and data from the indinavir trial is under review by the FDA for possible approval of this drug for pediatric patients. We are currently studying the long-term virological and immunological effects of therapy with these agents and in particular their ability to effect immune reconstitution. Preliminary results suggest that some patients on long-term therapy have immunologic improvement without sustained drops in their viral load. We are also investigating two novel immunomodulatory agents in HIV-infected children: recombinant IL-2 and HIV-1 immunogen vaccine. Preliminary results from the latter have suggested that high dose immunogen vaccine administration is associated with a decrease in the viral load, and immunologic responses are being examined. In addition to delineation of toxicity and antiviral activities, an intensive focus is directed toward assessment of quantitative and qualitative measures of immune function associated with these therapies. We have also recently initiated studies of the immunoreconstitution achieved with a combination regimen of highly active antiretroviral therapy (HAART) and of the combination of ddI (didanosine) and hydroxyurea, stavudine, and efavirenz as a protease-sparing salvage regimen. Preliminary results from this latter trial reveal that substantial drops in viral load can occur even in patients with substantial prior treatment experience. We are instituting trials of therapeutic drug monitoring (TDM) as a way of optimizing the use of available drugs; of tenofovir, a new nucleotide analogue reverse transcriptase inhibitor; and of capravirine. Longitudinal studies of neurocognitive function, brain imaging and immune measures in children receiving antiretroviral therapy are being conducted in addition to investigation of the pathophysiology of HIV encephalopathy. Psychosocial studies include investigation of correlates of psychosocial functioning and coping strategies in long term survivors, assessment of compliance to HAART regimens in relation to health belief systems, and studies of the effects of participating in the Starbright program in which they can communicate by computer with sick children in other hospitals around the country. 100% AIDS related.